Macrophage migration inhibitory factor (MIF) is a cytokine initially isolated based upon its ability to inhibit the in vitro random migration of macrophages (Bloom et al. Science 1966, 153, 80-2; David et al. PNAS 1966, 56, 72-7). Although MIF has been known since 1966 its precise function in the majority of cells is not known, but it seems that MIF is a critical upstream regulator of the innate and acquired immune response.
The human MIF cDNA was cloned in 1989 (Weiser et al., PNAS 1989, 86, 7522-6), and its genomic localization was mapped to chromosome 22. The product of the MIF gene is a amino acid protein of a molecular mass of 12.5 kDa. The protein is highly conserved with a sequence homology between human, mouse, rat, and bovine MIF between 90-96%. However, MIF has no significant sequence homology to any other protein. The three-dimensional structure of MIF is unlike any other cytokine or pituitary hormone. The protein crystallizes as a trimer of identical subunits. Each monomer contains two antiparallel alpha-helices that pack against a four-stranded beta-sheet. The monomer has an additional two beta-strands that interact with the beta-sheets of adjacent subunits to form the interface between monomers. The three beta-sheets are arranged to form a barrel containing a solvent-accessible channel that runs through the center of the protein along a molecular three-fold axis (Sun et al. PNAS 1996, 93, 5191-5196).
It was reported that MIF secretion from macrophages was induced at very low concentrations of glucocorticoid (Calandra et al. Nature 1995, 377, 68-71). However, as a proinflammatory cytokine, MIF also counter-regulates the effects of glucocorticoids and stimulates the secretion of other cytokines such as tumor necrosis factor TNF-α and interleukin IL-1β (Baugh et al, Crit. Care Med 2002, 30, S27-35) thus assuming a role in the pathogenesis of inflammatory and immune diseases. MIF is also directly associated with the growth of lymphoma, melanoma, and colon cancer (Nishihira et al. J Interferon Cytokine Res. 2000, 20:751-62).
MIF is a mediator of many pathologic conditions and thus associated with a variety of diseases including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), acute respiratory distress syndrome (ARDS), asthma, glomerulonephritis, IgA nephropathy, cancer, myocardial infarct (MI), and sepsis.
Polyclonal and monoclonal anti-MIF antibodies have been developed against recombinant human MIF (Shimizu et al., FEBS Lett. 1996; 381, 199-202; Kawaguchi et al., J. Leukoc. Biol. 1986, 39, 223-232, and Weiser et al., Cell. Immunol. 1985, 90, 167-78).
Anti-MIF antibodies have been suggested for therapeutic use to inhibit TNF-α release. Calandra et al., (J. Inflamm. 1995. 47, 39-51) reportedly used anti-MIF antibodies to protect animals from experimentally induced gram-negative and gram-positive septic shock. Anti-MIF antibodies were suggested as a means of therapy to modulate cytokine production in septic shock and other inflammatory disease states.
U.S. Pat. No. 6,645,493 discloses monoclonal anti-MIF antibodies derived from hybridoma cells, which neutralize the biological activity of MIF. It could be shown in an animal model that these mouse derived anti-MIF antibodies had a beneficial effect in the treatment of endotoxin induced shock. Some of the described anti-MIF antibodies (III.D.9, XIV.14.3 and XIV.15.5) were used in the present invention for comparative experiments.
US 2003/0235584 discloses methods of preparing high affinity antibodies to MIF in animals in which the MIF gene has been homozygously knocked-out.
Glycosylation-inhibiting factor (GIF) is a protein described by Galat et al. (Eur. J. Biochem. 1994, 224, 417-21). MIF and GIF are now recognized to be identical. Watarai et al. (PNAS 2000, 97, 13251-6) described polyclonal antibodies binding to different GIF epitopes to identify the biochemical nature of the posttranslational modification of GIF in Ts cells. Watarai et al (PNAS 2000, 97, 13251-6) reported that GIF occurs in different conformational isoforms in vitro. One type of isomer occurs by chemical modification of a single cysteine residue. The chemical modification leads to conformational changes within the GIF protein and changes its biological function.
Given the complexity of involvement of MIF in various diseases an elucidation of the function of epitope-specific anti-MIF antibodies and its use for therapeutic approaches is highly desirable. Therefore, there exists a need for epitope-specific anti-MIF antibodies, which inhibit human MIF biological function for the treatment of diseases and conditions mediated by MIF.